The Ubiquitin-Specific Protease Family: Master Regulators of Renal Fibrosis Pathogenesis and Therapeutic Targets

Ubiquitin-specific proteases (USPs) constitute the largest and most diverse family of deubiquitinating enzymes (DUBs), playing a pivotal role in maintaining protein homeostasis through reversible post-translational modifications (PTMs). Renal fibrosis represents the final common pathway of various chronic kidney diseases (CKDs), ultimately leading to irreversible nephron loss and end-stage renal disease (ESRD). With CKD affecting over 10% of the global adult population, fibrosis imposes a substantial clinical and economic burden. Despite this, effective antifibrotic therapies remain clinically elusive. Emerging evidence highlights the critical involvement of USPs in the pathogenesis of renal fibrosis through the potentiation of pro-fibrotic signaling pathways, inflammation, oxidative stress, cell cycle arrest and cellular senescence, as well as some other pathways. This review comprehensively summarizes the current understanding of USPs in renal fibrosis, detailing their structural characteristics, molecular mechanisms, and specific regulatory roles. Furthermore, we discuss recent advances in developing small-molecule USP inhibitors, providing novel insights into targeting the ubiquitin-proteasome system as a promising therapeutic strategy for combating renal fibrosis.